TBI Dose De-escalation for Fanconi Anemia - Full Text View

Sponsor:	Masonic Cancer Center, University of Minnesota
Information provided by:	Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:	NCT00352976

Purpose

This is a single arm, total body irradiation (TBI) trial. All patients will be prescribed TBI 300 cGy with the goal of evaluating secondary endpoints.

Condition	Intervention	Phase
Fanconi Anemia	Drug: Cyclophosphamide Drug: Fludarabine Drug: anti-thymocyte globulin (ATG) Procedure: Total Body Irradiation Procedure: Bone Marrow Transplantation Drug: Mycophenolate Mofetil Drug: Methylprednisolone	Phase II Phase III

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Crossover Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Total Body Irradiation Dose De-escalation Study in Patients With Fanconi Anemia Undergoing Alternate Donor Hematopoietic Cell Transplantation

Resource links provided by NLM:

Genetics Home Reference related topics: Fanconi anemia

MedlinePlus related topics: Anemia Bone Marrow Transplantation

Drug Information available for: Cyclophosphamide Prednisolone Prednisolone acetate Depo-medrol Fludarabine Fludarabine monophosphate Medrol veriderm Methylprednisolone Mycophenolate mofetil hydrochloride Mycophenolate Mofetil Prednisolone sodium phosphate Prednisolone Sodium Succinate Methylprednisolone Sodium Succinate Methylprednisolone hemisuccinate 6-Methylprednisolone

U.S. FDA Resources

Further study details as provided by Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:

Incidence of neutrophil recovery (absolute neutrophil count ≥500/µL for three consecutive days) . [ Time Frame: by day 42 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Incidence of grade ≥3 regimen related toxicity . [ Time Frame: at day 100 ] [ Designated as safety issue: Yes ]
Incidence of secondary graft failure at 100 days. [ Time Frame: 100 days ] [ Designated as safety issue: No ]
Incidence of acute graft-versus-host disease (GVHD) [ Time Frame: at 100 days. ] [ Designated as safety issue: No ]
Incidence of chronic GVHD . [ Time Frame: at one year ] [ Designated as safety issue: No ]
Probability of survival . [ Time Frame: at one year ] [ Designated as safety issue: No ]
Incidence of infections . [ Time Frame: at 100 days, 6 months and one year ] [ Designated as safety issue: No ]
Immune reconstitution . [ Time Frame: at 100 days, 6 month and one year ] [ Designated as safety issue: No ]

Estimated Enrollment:	45
Study Start Date:	May 2006
Estimated Study Completion Date:	May 2016
Estimated Primary Completion Date:	December 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Treatment with TBI Patients treated with total body irradiation, chemotherapy and transplant.	Drug: Cyclophosphamide Day -5 through Day -2, subjects will receive chemotherapy of Cyclophosphamide via central line (i.e. Hickman or Broviac),10 mg/kg intravenously (IV) Other Name: cytoxan Drug: Fludarabine Day -5 through Day -2 prior to transplant; subjects will receive chemotherapy of Fludarabine via central line (i.e. Hickman or Broviac),35 mg/m^2 intravenous (IV) Other Name: fludara Drug: anti-thymocyte globulin (ATG) Day -5 through Day -1, subjects will receive ATG via central line (i.e. Hickman or Broviac), 30 mg/kg/day IV Other Name: Thymoglobulin Procedure: Total Body Irradiation total body irradiation (300 cGy) with thymic shielding will be given six days before the stem cells are given (day -6). Thymic shielding is done by placing a piece of lead on the chest during the irradiation treatment so that the irradiation beams do not go to the thymus. Other Name: Radiation Therapy, Therapeutic radiation Procedure: Bone Marrow Transplantation A target of 5 * 10^6/kg and a minimum of 4 * 10^6 CD34+ cell/kg recipient weight will be collected by apheresis and used for transplant. In most cases this dose will be recovered in a single apheresis; however, a second or rarely third apheresis performed on the following days may be required to achieve the minimum dose. Other Name: Stem Cell transplantation Drug: Mycophenolate Mofetil Patients will receive MMF therapy beginning on day -3 through day +30 or for 7 days after engraftment, whichever day is later, if no acute graft-versus-host disease (GVHD). Engraftment is defined as 1st day of 3 consecutive days of absolute neutrophil count [ANC] > 0.5 * 10^9/L. MMF will be given at a dose of 15 mg/kg/dose every 8 hours by mouth(to a maximum dose of 1 gram). Other Name: MMF Drug: Methylprednisolone Methylprednisolone (MP) 2 mg/kg/day intravenously every 24 hours will be given from day -5 until day -1 as a premedication for antithymocyte globulin (ATG). Equine ATG 30 mg/kg/day will be administered after MP on days -5, -4, -3, -2 and -1 preceding transplant. Other Name: Medrol

Arms

Assigned Interventions

Experimental: Treatment with TBI

Patients treated with total body irradiation, chemotherapy and transplant.

Drug: Cyclophosphamide

Day -5 through Day -2, subjects will receive chemotherapy of Cyclophosphamide via central line (i.e. Hickman or Broviac),10 mg/kg intravenously (IV)

Other Name: cytoxan

Drug: Fludarabine

Day -5 through Day -2 prior to transplant; subjects will receive chemotherapy of Fludarabine via central line (i.e. Hickman or Broviac),35 mg/m^2 intravenous (IV)

Other Name: fludara

Drug: anti-thymocyte globulin (ATG)

Day -5 through Day -1, subjects will receive ATG via central line (i.e. Hickman or Broviac), 30 mg/kg/day IV

Other Name: Thymoglobulin

Procedure: Total Body Irradiation

total body irradiation (300 cGy) with thymic shielding will be given six days before the stem cells are given (day -6). Thymic shielding is done by placing a piece of lead on the chest during the irradiation treatment so that the irradiation beams do not go to the thymus.

Other Name: Radiation Therapy, Therapeutic radiation

Procedure: Bone Marrow Transplantation

A target of 5 * 10^6/kg and a minimum of 4 * 10^6 CD34+ cell/kg recipient weight will be collected by apheresis and used for transplant. In most cases this dose will be recovered in a single apheresis; however, a second or rarely third apheresis performed on the following days may be required to achieve the minimum dose.

Other Name: Stem Cell transplantation

Drug: Mycophenolate Mofetil

Patients will receive MMF therapy beginning on day -3 through day +30 or for 7 days after engraftment, whichever day is later, if no acute graft-versus-host disease (GVHD). Engraftment is defined as 1st day of 3 consecutive days of absolute neutrophil count [ANC] > 0.5 * 10^9/L. MMF will be given at a dose of 15 mg/kg/dose every 8 hours by mouth(to a maximum dose of 1 gram).

Other Name: MMF

Drug: Methylprednisolone

Methylprednisolone (MP) 2 mg/kg/day intravenously every 24 hours will be given from day -5 until day -1 as a premedication for antithymocyte globulin (ATG). Equine ATG 30 mg/kg/day will be administered after MP on days -5, -4, -3, -2 and -1 preceding transplant.

Other Name: Medrol

Detailed Description:

Study Treatment: Patients will receive voriconazole (antifungal therapy) by mouth beginning 1 month prior to conditioning therapy, if possible. 1) The subject is to receive total body irradiation (300 cGy) with thymic shielding; it will be given six days before the stem cells are given (day -6). 2) Day -5 through Day -2, subjects will receive a chemotherapy regimen of Fludarabine, Cyclophosphamide, anti-thymocyte globulin (ATG), and Methylprednisone via central line (i.e. Hickman or Broviac). On day -1, subjects will receive ATG and Methylprednisone. 3) Starting Day -3, patients will receive CSA therapy beginning on day -3 with a taper commencing on day +180 and also mycophenolate mofetil (MMF) through day +30 or for 7 days after engraftment, whichever day is later, if no acute graft-versus-host disease (GVHD). 4) If the subject is receiving bone marrow or "peripheral" stem cells (cells collected from the donor's arm via a cell separator), on the day of transplantation, the stem cells taken from the donor will be put into a machine which will separate the lymphocytes (the cells that cause graft-versus-host disease [GVHD]) from the stem cells. If the subject is receiving an umbilical cord blood, the lymphocytes will not be removed because the risk of GVHD is not as high. Otherwise all patients will receive the same treatment. The stem cells are given as an infusion into the subject's existing catheter over 1-2 hours on day 0.5. On the day after transplant (day +1) subjects will be given G-CSF to stimulate the growth of the transplanted cells. 6. While receiving treatment and until the subject's blood counts recover he/she will have daily blood tests, and several bone marrow biopsies and aspirates. After recovery, subjects will be seen once a month for a health assessment and blood tests until at least 3 months after the cells have been infused. Additional blood tests or assessments may be done as medically indicated.

Eligibility

Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Meeting the definition of standard risk or high risk Fanconi anemia as defined in the next two sections:

Standard risk patients must be <18 years of age with a diagnosis of Fanconi anemia with aplastic anemia (AA), myelodysplastic syndrome without excess blasts, or high risk genotype as defined below:
- Aplastic anemia is defined as having at least one of the following when not receiving growth factors or transfusions:
  - platelet count <20 * 10^9/L
  - ANC <5 * 10^8/L
  - Hemoglobin <8 g/dL
- Myelodysplastic syndrome with multilineage dysplasia with or without chromosomal anomalies
- High risk genotype (e.g. IVS-4 or exon 14 FANCC mutations, or BRCA1 or 2 mutations)
High risk patients must have one or more of the following high risk features:
- History at any time of systemic fungal or gram negative infection
- Severe renal disease with a creatinine clearance <40 mL/min
- Age > 18 years
Patients must have an ≤1 antigen mismatched HLA-A, B, DRB1 unrelated donor or ≤1 antigen mismatched related (non-HLA-matched sibling) or <2 antigen mismatched unrelated umbilical cord blood (UCB) donor. Patients and donors will be typed for HLA-A and B using intermediate or high resolution molecular techniques and for DRB1 using high resolution molecular typing.
Adequate major organ function including:
- Cardiac: ejection fraction >45%
- Hepatic: bilirubin, AST or ALT, ALP <5 x normal
- Karnofsky performance status >70% or Lansky >50 (if < 16 years of age)
Women of child-bearing age must be using adequate birth control and have a negative pregnancy test.
Written consent.

Exclusion Criteria:

Available HLA-genotypically identical related donor in standard risk patients.
Active central nervous system (CNS) leukemia at time of study enrollment.
History of squamous cell carcinoma of the head/neck/cervix within previous 2 years.
Prior radiation therapy that prevents further total body irradiation (TBI).

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00352976

Contacts

Contact: Margaret L MacMillan, M.D.

612-626-2778

macmi002@umn.edu

Locations

United States, Minnesota
University of Minnesota Medical Center	Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Margaret L MacMillan, M.D. 612-626-2778 macmi002@umn.edu

Sponsors and Collaborators

Masonic Cancer Center, University of Minnesota

Investigators

Principal Investigator:

Margaret L MacMillan, M.D.

University of Minnesota Medical Center

More Information

No publications provided

Responsible Party:	MacMillan, Margaret L., MD, Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:	NCT00352976 History of Changes
Other Study ID Numbers:	MT2006-05, 0605M85788
Study First Received:	July 14, 2006
Last Updated:	September 6, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by Masonic Cancer Center, University of Minnesota:

Bone Marrow transplant
stem cell transplant
cord blood transplant
total body irradiation
thymic shielding

Additional relevant MeSH terms:

Anemia
Fanconi Anemia
Fanconi Syndrome
Hematologic Diseases
Anemia, Hypoplastic, Congenital
Anemia, Aplastic
Bone Marrow Diseases
Genetic Diseases, Inborn
DNA Repair-Deficiency Disorders
Metabolic Diseases
Kidney Diseases
Urologic Diseases
Renal Tubular Transport, Inborn Errors
Metabolism, Inborn Errors
Antilymphocyte Serum

Cyclophosphamide
Fludarabine monophosphate
Mycophenolate mofetil
Fludarabine
Methylprednisolone Hemisuccinate
Prednisolone
Mycophenolic Acid
Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone
Prednisolone phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on February 13, 2012